Articular cartilage plays an essential role in the movement of mammalian joints. It provides a superior smooth surface between adjacent bones, allowing for near-frictionless motion of joints. Synovial fluid within the joint cavity serves as a lubricant. It is the articular cartilage that spreads compressive stresses over the articular plate surfaces of the joint, thus protecting weight-bearing bones from shattering or deteriorating.
Articular cartilage is composed of chondrocytes embedded in an extracellular matrix of proteoglycans, collagen, and small molecular weight glycoproteins. Chondrocytes are cartilage cells embedded in lacunae within the cartilage matrix. Proteoglycans are essential in maintaining strength of the cartilage tissue so that it can withstand compression. Collagen provides the tissue with tensile strength and resistance to shear. In a healthy joint, the extracellular matrix is maintained by a balance between the synthesis and secretion of these macromolecules by chondrocytes and their subsequent degradation by proteolytic enzymes such as proteoglycanases and metalloproteinases, which are also synthesized and secreted by chondrocytes. Damage to the cartilage of the articular surface can disrupt this equilibrium, such that degradation exceeds the ability of chondrocytes to synthesize macromolecules necessary for repair of the cartilage tissues. Chronic disruption of the equilibrium between synthesis and degradation of cartilage matrix macromolecules is associated with the development of osteoarthritis.
Osteoarthritis (OA), also known as degenerative joint disease, is the most common form of arthritis and results from the gradual breakdown of cartilage that accompanies aging. Typically, OA follows trauma or chronic joint injury due to some other type of arthritis such as rheumatoid arthritis. Alternatively, OA can result from overuse of a particular joint. OA may be classified as: primary, in which no underlying cause is apparent; secondary, which is associated with a predisposing factor such as trauma, repetitive stress (occupation, sports), congenital abnormality, metabolic disorder, or other bone/joint disease; and erosive, a syndrome characterized by periods of acute inflammation and progressive destruction of the joints occurring most often in middle-aged women. OA most is most commonly prevalent in the joints of the fingers, hips, knees, spine, base of the thumb, and big toe. Clinically, OA is characterized by joint pain, tenderness, and limitation of movement, crepitus, and inexorably progressive disability. It can be present in just one of these joints or in all of them. Although most body tissues can make repairs following an injury, cartilage self-repair is hampered by a limited blood supply and the lack of an effective mechanism for cartilage re-growth.
In osteoarthritis, the first alteration in the joint, which takes place over decades, is a roughening of articular cartilage followed by pitting, ulceration, and progressive loss of cartilage surface. Proinflammatory cytokines accelerate degradation of the cartilage matrix. Persistent inflammation produces symptoms and damages tissue resulting in loss of cartilage, erosion of bone matter, and subluxation of the joint. There is compelling evidence that soluble inflammatory mediators (i.e., molecules that are released by immune cells during times when harmful agents invade our body) such as cytokines, interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a), are involved in the osteoarthritis process. By inducing the synthesis of proteolytic enzymes, cytokines interfere with the action of growth factors such as the insulin growth factor-I (IGF-1) binding proteins. Moreover, the inflammatory cytokines have the ability to suppress the synthesis of type II collagen, characteristic of hyaline cartilage, while augmenting the synthesis of type I collagen, characteristic of fibroblast cells. In addition, IL-1 reduces aggrecan synthesis, the macromolecule largely responsible for the mechanical properties of articular cartilage.
Historically, treatment of osteoarthritis and articular cartilage injuries has been limited to pain relief, reduction of joint loading, physical therapy, and orthopedic surgery, all of which are aimed at symptomatic relief rather than treatment of the underlying pathologic disorder. More recently, osteoarthritis research has concentrated on development of chondroprotective methods. Such methods involve long-term therapeutic treatment aimed at preserving or stimulating cartilage formation. Present treatment of arthritis includes first line drugs for control of pain and inflammation classified as non-steroidal anti-inflammatory drugs (NSAIDs), such as, aspirin, ibuprofen, naproxen, and methotrexate. Secondary treatments include corticosteroids, slow acting anti-rheumatic drugs (SAARDs) or disease modifying drugs (DMs), such as, pencillinamine, cyclophosphamide, gold salts, azothipprine, and levamisole. Although NSAIDS are one of the major groups of drugs in terms of sales and use for the management of OA among the general population, their side effects have become an issue in the risk/benefit determination, particularly in the elderly. Depending upon individual circumstances, NSAIDS may cause gastrointestinal hemorrhage, ulceration, or perforation, while some are associated with bone marrow depression, several cause fluid retention, and may contribute to renal failure. These effects are particularly important because such treatments are often long-term. While the previously mentioned drugs have met with some degree of success in the preventative treatment of osteoarthritis, new and improved methods and pharmaceutical compositions are constantly being sought which may effectively reduce the progression of lesion and cartilage degradation in a mammal suffering from osteoarthritis. It is therefore an object of the present invention to provide a methodology for effectively treating arthritis, degenerative disc disease, and cartilage diseases.
Herbal medicines for treatment of a variety of ailments in mammals are known. Typically, such herbal medicines are obtained as the active compound(s) by extraction from plant tissues. For example, it is known to treat degenerative musculoskeletal diseases such as rheumatoid arthritis and osteoarthritis in an animal, typically a human, by enteric administration of a therapeutically effective amount of the beneficiated extracts of the plants Withania somnifera, Boswellia serrata, Curcuma longa, and Zingiber officinale in a predetermined proportion to each other. It is also known to treat inflammation in a patient by oral administration of an effective dose of a pharmaceutical composition containing essential oils extracted from tissues of Curcuma domestica, or Curcuma xanthorrhiza, or both oils and curcuminoid substantially free of bis-desmethoxycurcumin. Edible herbal compositions containing a mixture of at least three, and as many as seven, herbs selected from Tanacetum parthenium, Zingibar officinale, Curcuma longa, Coriandrum sativum, Centella asiatica, Oenothera biennis, Valeriana officinalis, have been used as anti-inflammatory agents for alleviation of arthritis and gout is also known
It is also known that acetylglucosamine and the individual compound glucuronic acid can be combined with plant extracts selected from the group consisting of Vaccinum Myrtillus, Sylibum Marianum, Echinacea Angustifolia, Aesculus Hippocastanum, Calendula Officinalis, Centella Asiatica, Hamamelis Virginiana, Citrus Aurantium Amara, Citrus Aurantium Dulcis, Citrus Limonium, Equisetum Arvense, Glycyrritia Glabbra, Aloe Vera, Ruta Graveolans, Vitis Vinifera and Terminalia Sericea for cosmetic, pharmaceutic and dietic use. Also, it is known that COX-2 can be inhibited using an organic extract isolated from edible plants.
Although the use of various herbs has been described in related areas, the use of a parenteral composition of Centella extract for the treatment of osteoarthritis, cartilage injury, and degenerative disc disease has never previously been described.
The plant Centella Asiatica can be found throughout Asia and is commonly employed in skin disease. Reports to support these properties have been published as early as in 1971. The three active components of Centella extract, asiaticoside, asiatic acid, and madecassic acid, were also identified and tested. The specific role that each of these component compounds plays in the biological activity of Centella however, is unknown. The crude extract as well as the active components were claimed to be effective not only in the treatment of leprosy, but also in slow-healing wounds, surgical lesions, phlebitis, and leg ulcers (Lille Med, 1971, 17:Suppl 3:574-9). The active components as well as the crude extracts have been reported to increase collagen synthesis and cellular proliferation (Contact Dermatitis, 1993, 39(4): 175-9; Eur J Dermatol, 1999, 9(4): 289-96; Ital J Biochem, 1988, 37(2), 69-77). They also enhanced the rate of dermal wound healing in rats (Indian J. Exp. Boil, 1996, 34(12): 1208-11). In clinical studies, extracts from Centella have been claimed to be beneficial in preventing as well as reducing scarring (Bossee J P, et al: Clinical Study of a new anti-keloid agent). One important feature that could make Centella extracts attractive for use in wound healing treatment is that repeated applications on damaged skin did not lead to development of contact sensitivity (Lille Med, 1971, 17:Suppl 3:574-9). Numerous studies have elucidated the wound healing and anti-scarring properties of Centella. Isolated extracts of this plant have been used orally to treat migraines, arthritis, and bronchial complaints. There are no reports discussing the use of a parenteral composition of Centella extract for treatment of arthritis and other cartilage and disc related disease.
There is a constant need in this art for new compositions for treating arthritis and cartilage degeneration, as well as new methods of treating such conditions.